IL-10 polymorphisms +434T/C, +504G/T, and -2849C/T may predispose to tubulointersititial nephritis and uveitis in pediatric population
IL-10 polymorphisms +434T/C, +504G/T, and -2849C/T may predispose to tubulointersititial nephritis and uveitis in pediatric population
Sari Rytk o?nen 0 1
Jarmo Ritari 1
Juha Per a?saari 1
Ville Saarela 1
Matti Nuutinen 0 1
Timo JahnukainenID 1
0 PEDEGO Research Unit and Medical Research Center (MRC), University of Oulu and Oulu University Hospital , Oulu , Finland , 2 Clinical Laboratory, Finnish Red Cross Blood Service , Helsinki, Finland, 3 Ville Saarela , Department of Ophthalmology, Oulu University Hospital , Finland, 4 Timo Jahnukainen , Department of Pediatric Nephrology and Transplantation, New Children's Hospital, University of Helsinki and Helsinki University Hospital , Helsinki , Finland
1 Editor: Cinzia Ciccacci, Tor Vergata University , ITALY
A significant difference in the frequency of IL-10+434T and +504G alleles was found
between TIN/TINU patients and control population. Genotype -2849TT was more frequently
Data Availability Statement: All relevant data are
within the manuscript and its Supporting
Funding: This study has been supported by the
Foundation for Pediatric Research, the Pa?ivikki and
Sakari Sohlberg Foundation, Finnish Medical
Foundation and the Alma and K.A. Snellman
Foundation, Oulu, Finland. The funders had no role
in study design, data collection and analysis,
decision to publish, or preparation of the
Competing interests: The authors have declared
that no competing interests exist.
present in patients with TINU syndrome than in the reference subjects. Genetic variation in
the inflammatory mediators may predispose to autoimmune nephritis and uveitis.
Tubulointerstitial nephritis (TIN) is a relatively rare but significant cause of acute renal
insufficiency (AKI) among children and adults . It is an inflammatory disease, possibly of
autoimmune origin [2?5], primarily affecting the renal interstitium and tubular wall without
significant glomerular or vascular involvement [6,7]. It can sometimes be accompanied by
uveal inflammation (TINU syndrome) which is typically anterior and bilateral [8, 9].
TIN may be triggered by several causes including infections and medications, or etiology
can be idiopathic . TIN and uveitis separately can also be associated with systemic
immunologic conditions such as sarcoidosis, systemic lupus erythematosus (SLE) or inflammatory
bowel disease (IBD) [11?13]. Previous studies have shown evidence of polymorphisms in
interleukin 10 (IL-10) and tumor necrosis factor ? (TNF-?) coding genes in patients with
non-infectious uveitis (NIU) [14, 15]. There are also recent data showing that polymorphisms
in these two inflammatory regulators are enriched in patients with inflammatory bowel disease
and children with wheezing [16?19]. In this study, the aim was to investigate the frequency of
IL-10 and TNF-? single nucleotide polymorphisms (SNPs) in a national cohort of well-defined
children and adolescents with TIN/ TINU syndrome compared to Finnish reference
Materials and methods
The study was approved by the Ethics Committee of Helsinki University Hospital and followed
the tenets of the Declaration of Helsinki. Written informed consent was obtained from all
patients and/or parents before the study commenced.
This study was part of our previous nationwide study evaluating HLA associations in TIN/
TINU patients [9, 20] and the patient demographics has been reported before. Briefly, the
inclusion criteria were biopsy-proven TIN in pediatric patients under 16 years of age. The
study cohort was collected from all five university hospitals in Finland between 2008 and 2011.
Meticulous work-up was done to exclude possible underlying conditions, such as
druginduced TIN, respiratory infection, sarcoidosis, connective tissue disorder and lymphoma.
Uveitis was classified according to standardization of uveitis nomenclature (SUN) criteria. All
patients were followed up by a pediatric nephrologist and ophthalmologist for at least one year
after the diagnosis of TIN [9, 20, 21].
A total of 30 patients were enrolled (17 boys, 13 girls). Nineteen patients (63%) had uveitis
(TINU syndrome) and 15 (50%) of them had chronic uveitis. The median age at the time of
diagnosis was 12.5 (9.4?14.7) years. Demographic data is presented in Table 1.
The targeted single nucleotide polymorphisms from our TIN patient cohort were IL-10
+434T/C, +504G/T, -1082G/A, -2849C/T and TNF-? -308G/A, -238G/A, -857C/T. The primers
used in polymerase chain reaction (PCR) to amplify DNA fragments containing our SNPs of
interest are presented in Table 2. Genomic DNA samples were sequenced in Oulu University
DNA sequencing core facility laboratory with the following method: The PCR amplifications
were carried out in a total volume of 11?L, which contained 20 ng genomic DNA, 25 mM
MgCl2, 2 mM dNTP mix, 5 ?M of each primer, 0.4 unit Maxima Hot Start Taq DNA
polymerase and 1 x Hot Start PCR Buffer (Fermentas). PCR products were screened using QIA excel
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Advanced System (QIAGEN) to confirm the successful amplification. Agencourt AMPure
protocol (Beckman Coulter) was used to purify PCR products for sequencing. Finally, the
samples were sequenced using ABI3500xL Genetic Analyzer and BigDye Terminator vs.1.1
reagents (Life Technologies). Chromatograms were analyzed by using the Chromas Lite 2.1
The frequency of these SNPs was analyzed in the whole study population and in the
subgroups of patients with TIN, TINU and TINU with chronic uveitis. Control group (n = 686)
frequencies for the IL-10 and TNF-? SNP were obtained from both Illumina Immunochip
 analysis of 587 Finnish siblings and from the 1000 Genomes Project Finnish population
subset (n = 99) . The Immunochip hybridization and genotype calling were performed at
the Institute for Molecular Medicine Finland (Helsinki, Finland) according to manufacturer?s
instructions. Since the TNF-? SNP -857 / rs1799724 and IL-10 SNP -2849 / rs6703630 were
not included in the Immunochip array, their frequencies were imputed using Impute2 v3.2.3
software  with default settings and 1000GP_Phase3 as the reference data set. The imputed
sequence intervals in GRCh37 Human genome build were 206000000?208000000 for
chromosome 1 (rs6703630) and 30500000?32600000 for chromosome 6 (rs1799724).
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Statistical analyses were carried out with R v3.2.2 (R Core Team 2015). Fisher?s exact test was
performed for significance of association for SNP frequencies between patients and controls.
The reference SNP frequencies used in Fisher?s test were weighted by the respective sample
sizes from the Immunochip (n = 587) and 1000 Genomes (n = 99) data sets. Since the
Immunochip data consisted of sibling pairs, the sample size number used in Fisher?s test was halved
to take into account the fact that relatedness reduces the effective sample size. Logistic
regression was performed for SNP genotype association using the Immunochip sibling cohort as a
reference. Finally, all raw p-values were adjusted for multiple testing by the Bonferroni
The homozygous minor allele in IL-10 +434T (rs2222202) and IL-10+504G (rs3024490) was
found in all patients with TIN/TINU syndrome (Table 3). The frequency of these minor alleles
in the control population was 44% and 23%, respectively (p <0.001). The presence of minor
allele in IL-10 -2849T did not differ significantly between the cases and the controls (p = 0.33)
(Table 3). However, the homozygous -2849TT genotype was found more frequently
(p = 0.004) in the patients (17%) than in the controls (0.01%) (Table 4). There were no
statistical differences in any of the studied TNF-? alleles between TIN/TINU patients and control
population (Table 3, S1 Table).
In the subgroup analysis, a significant increase in the allele frequency of IL-10+434T
(rs2222202) was found in patients with isolated nephritis (p <0.001), TINU syndrome (p <
0.001) and TINU with chronic uveitis (p <0.001) when compared to the reference population
(Table 4). IL-10+504G (rs3024490) minor allele was present more often in TINU patients
(p = 0.004) but not in subgroups with isolated TIN (p = 0.5) or TINU syndrome with chronic
uveitis (p = 0.07) (Table 4).
In SNP -2849 (rs6703630) a significant difference in genotype frequency TT was found in
patients with TINU syndrome (p = 0.017) and TINU syndrome with chronic uveitis (p = 0.01)
when compared to the reference population (Table 4).
In the present study, we aimed to investigate the frequency of IL-10 and TNF-?
polymorphisms in a cohort of Finnish pediatric patients with idiopathic TIN/TINU syndrome. All
patients with either isolated nephritis or TINU syndrome were homozygous carriers of the
IL10 +434T and +504G minor alleles, which suggests that these SNPs may predispose to TIN
and/or TINU. In addition to IL-10 +434T and +504G minor alleles, the patients with uveitis
and chronic uveitis had significantly more frequently IL-10 -2849TT genotype than Finnish
control population. Despite the high occurrence of uveitis in the present study population,
none of the previously reported TNF-? SNPs -308G/A, -238G/A, -857C/T were found in this
cohort. Our results suggest that IL-10 polymorphisms may have a role in susceptibility to TIN/
TINU while genetic variation in TNF-? gene may be connected to isolated uveitis.
It is obvious that tendency for uveitis with or without tubulointerstitial nephritis is
dependent on genetic factors. We, among others, have previously shown an association between
HLA haplotypes and uveitis and/or TIN [2, 3, 25, 26]. Based on our present findings,
variability in the IL-10 gene may predispose to TIN/TINU in pediatric population. IL-10 production
is stimulated by various exogenous and endogenous factors, but it has also been shown to
be under genetic control with association to different SNPs in several independent studies
[27?29]. Different allele and genotype variations alter cytokine profiles influencing the
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development and severity of various diseases, as documented in SLE, tuberculosis and several
other infectious diseases (IL-10 overexpression) [30?36], and rheumatoid arthritis and asthma
(IL-10 downregulation) [19, 37?39]. Polymorphisms in inflammatory response regulating
genes have been reported among patients with uveitis [40?42]. Atan et al. have previously
shown a significant association between IL-10?2849, +434, +504 minor allele frequencies and
non-infectious uveitis (NIU) in a cohort of 192 patients . The SNPs +434 (rs2222202) and
+504 (rs3024490) located in introns are in regulatory regions, and may influence the
expression of mRNA and/or protein. The same point is related to SNP-2849 (rs6703630) located in
the 5?UTR region. According to the Genotype-Tissue Expression (GTEx) database (https://
gtexportal.org), IL-10 mRNA expression is increased significantly in whole blood samples
from human subjects with minor allele SNPs +434 (rs2222202), +504 (rs3024490), and -2849
(rs6703630). This data indicates, that these homozygous minor alleles have impact on gene
regulation separately, however, their cooperative action and influence on IL-10 level remain
In the present study, previously reported, association between TNF-? alleles -308AA and
-238AA, IL-10 SNP -1082AA and TIN/TINU could not be found [14, 15]. All patients,
including those with chronic uveitis, had -238GG and -308GG genotype, which suggests that in TIN
patients the studied genetic variation in TNF-? does not have any influence on uveitis risk.
The genetic background in TIN/TINU patients is probably different from patients with
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OR, Odds ratio; SNP, Single nucleotide polymorphism; Pts, Patients; TIN, Tubulointerstitial nephritis; TINU, Tubulointerstitial nephritis with uveitis syndrome; IL-10,
Interleukin 10; CI, Confidence interval. Control group for allele frequency 2n = 785. Control group for genotype frequency consist only of Illumina Immunochip
population, n = 257; Genotype frequency analysis was done with logistic regression; p-values are adjusted for multiple testing by the Bonferroni method.
heterozygous patients n = 9/30% vs. controls 21%
#homozygous patients n = 5/17% vs. controls 0.01%
?Odds ratio for minor allele frequency was calculated when applicable. No OR for SNPs IL-10 +434 and IL-10 +504 were calculated because the other allele frequency
isolated uveitis. This is also supported by our previous finding in this same study population
showing that none of the patients had the HLA-DRB1 15 genotype, which has been suggested
to be associated with increased risk for uveitis [43, 44] and is relatively common in the Finnish
population (15%) . It is also likely, that the association between HLA genotype as well as
genetic variation in cytokine genes and uveitis appear to depend on study population and
ethnicity . In previous studies, the patient cohorts have been rather heterogeneous consisting
of patients with varying causes of uveitis, such as sarcoidosis, Bechet?s disease, sympathetic
ophthalmia, intermediated uveitis, white dots with or without inflammation, and the age range
of the patients was wide. [14, 15]. In the present study, all patients had biopsy proven nephritis
and systemic diseases and infectious agents were excluded. In addition, the patients were
prospectively followed-up by pediatrician and ophthalmologist at least 12 months from initial
diagnosis, which is likely to improve the reliability of our findings. It is also of note that in the
present study, all patients had TIN and approximately half of them had chronic uveitis. The
presence of nephritis has not been reported in majority of the previous studies.
The major caveat of the study is the relatively small study population. TIN/TINU is a
relatively rare entity. We have collected patients from all university hospitals in Finland and this is
one of the largest pediatric data that has been published. In addition, all patients were
evaluated carefully and followed up prospectively using the same protocol. Another weakness is that
we did not measure serum levels of IL-10 and TNF-?, and therefore based on our data, we are
not able to draw any conclusions about the clinical relevance of the identified SNPs in this
In conclusion, IL-10 gene polymorphisms +434T/C, +504G/T, and genotype -2849TT were
found in a majority of the TIN/TINU patients while the frequency of none of the previously
reported TNF? SNPs differed from control population. The clinical importance of this finding
remains to be studied.
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S1 Table. Clinical information and TNFa -308, TNFa -238, TNFa -857, IL10?2849, IL10?
1082, IL10 +434, IL10 +504 genotype of each patient.
The authors thank Mari Taipale from the DNA Sequencing and Expression Analysis Center,
Biocenter Oulu, University of Oulu, for executing the sequencing of the patient samples.
Conceptualization: Sari Rytko?nen, Ville Saarela, Matti Nuutinen, Timo Jahnukainen.
Formal analysis: Jarmo Ritari, Juha Pera?saari.
Funding acquisition: Timo Jahnukainen.
Investigation: Sari Rytko?nen.
Supervision: Matti Nuutinen, Timo Jahnukainen.
Writing ? original draft: Sari Rytko?nen.
Writing ? review & editing: Jarmo Ritari, Juha Pera?saari, Ville Saarela, Matti Nuutinen, Timo
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